Obesity treatment

Abstract

The invention provides the anti-myostatin antibody GYM329 / emugrobart for use in the treatment, prevention or reduction of obesity or overweight or weight maintenance.

Description

[0001] P60000-WQ-1

[0002] Obesity treatment

[0003] The invention relates to the use of the anti -myo statin antibody GYM329 / emugrobart for the treatment of obesity.

[0004] Obesity is a complex multifactorial disease characterized by the accumulation of surplus body fat, stored not only in the adipose tissue, but also ectopically in organs such as the liver and in muscles. This condition is not merely a cosmetic concern; it significantly increases the risk of developing other diseases and health problems, including heart disease, diabetes, high blood pressure, certain types of cancer, and osteoarthritis (Safaei et al 2021). These conditions contribute to substantial disability and premature death. People are classified as having obesity when their body mass index (BMI) is > 30 kg / m2. However, this measure does not directly assess body fat, and it may overestimate body fat in those with leaner body mass (e.g., athletes) while underestimating it in the elderly or other individuals who have lost considerable muscle mass (Tafeit et al., Exp Biol Med 2019 Aug; 244(11): 873-879).

[0005] The worldwide impact of obesity is significant. According to the World Health Organization (WHO), obesity has nearly tripled worldwide since 1975. In 2016, more than 2 billion people were overweight or had obesity (Meera and Popkin, World Bank Publications 2020). This represents about 44% of the world's adult population. Furthermore, 20% of children over the age of five were overweight or had obesity.

[0006] Obesity is, however, preventable and treatable. Many individuals having obesity have made many attempts to lose weight through lifestyle changes and are often successful in short term weight reduction; however, maintenance of weight loss long term is rare (De Lorenzo et al., Nutrition 2020 Mar:71:110615).

[0007] Changes to diet (energy intake) as well as physical exercise are the main treatments for obesity recommended by health professionals (Bray et al., Endocr Rev 2018 Apr 1;39(2):79-132). Medications can be used, along with a suitable diet, to reduce appetite or decrease fat absorption (Angelidi et al., Endocrine Reviews, Volume 43, Issue 3, June 2022, Pages 507-557). If diet, exercise, and medication are not effective, gastric balloon or other intragastric devices may produce weight loss, but these devices must be removed after 6 months. Bariatric surgery procedures such as sleeve gastrectomy and Roux-en-Y gastric bypass reduce appetite and can produce durable weight loss in most patients, but these procedures require long-term follow-up (FU) and nutritional support (Bray et al., Endocr Rev 2018 Apr 1;39(2):79-132).

[0008] Incretin hormones are peptides that are secreted in the gut in response to nutrient intake and stimulate insulin secretion in the presence of elevated blood glucose (Nauck and Meier, Diabetes Obes Metab 2018 Feb:20 Suppl 1:5-21). Glucose-dependent insulinotropicpoly peptide (GIP) and glucagon-like peptide- 1 (GLP-1) and their receptors are well characterized incretins, and mimetics of these hormones are now available for pharmacotherapy (Qiyuan Keith Liu, Front. Endocrinol., Sec. Diabetes: Molecular Mechanisms, Volume 15, 2024).

[0009] In cretin therapies, which include GLP-1 receptor agonists (RAs) and GLP-1 / GIP dual agonists, were primarily developed for the treatment of type 2 diabetes mellitus (T2DM) (Angelidi et al., Endocrine Reviews, Volume 43, Issue 3, June 2022, Pages 507-557). Two agents originally approved for diabetes (semaglutide and tirzepatide) received recent approval as Wegovy® (semaglutide) and Zepbound® and Mounjaro® (tirzepatide) for chronic weight management in adults with obesity or overweight in the presence of at least one weight-related comorbidity Semaglutide has been approved for the indication of secondary prevention of cardiovascular disease in people without diabetes. Glucagon-like pep-tide-1 receptor (GLP-1R) agonists work by mimicking the functions of the body's natural incretin hormones, which help to regulate glucose metabolism. The incretin hormones, now often termed nutrient stimulated hormones, have pleiotropic effects and act on many organs. They have central effects to mediate changes in appetite, increasing satiety and promoting less food intake and thus weight loss. Native GLP delays gastric emptying, promotes natriu-resis and diuresis, has cardioprotective effects, is anti-inflammatory, and lessens platelet hypercoagulability, among other properties (Drucker & Holst, Diabetologia 2023 Oct;66(10): 1765-1779). These effects can lead to a decrease in caloric intake and weight loss and are to be used in conjunction with a calorie reduced diet and physical exercise. It is important to note that while these therapies can aid in weight loss, they are not a substitute for lifestyle modifications.

[0010] Even in the era of effective obesity medications, updated guidelines still recommend beginning and maintaining behavioral modifications, and where required, adding pharmacological or surgical intervention. Behavioral modifications include nutritional therapy, physical activity, stress reduction and sleep improvement (Busetto et al., Nat Med 2024 Sep; 30(9):2395-2399).

[0011] One undesired aspect of intentional weight loss, regardless of whether diet-induced, or via bariatric surgery or pharmacologic intervention, is the loss of lean muscle mass accompanying total body weight loss (Santini et al., Obesity 2023 Jan;31(l):74-82). In studies with the incretins semaglutide or tirzepatide in patients with obesity, between 25% and 44% of weight loss was due to a decrease in lean mass (Ida et al., Curr Diabetes Rev 2021 ; 17(3): 293-303). In the second year of treatment, weight loss plateaued, and upon treatment withdrawal, rapid weight regain was observed (approximately 65%) (Rubino et al., JAMA 2021:325(14): 1414-1425), notably, with restoration of fat mass (Yates et al., Diabetes, Obesity and Metabolism, Vol 26, Issue 3, p. 1008-1015; March 2024).The significance of muscle mass loss associated with weight loss for general health is discussed controversially. It may be simply a physiological reaction to having to carry less body weight (Conte et al., JAMA 2024 Jul 2;332(l):9-10024), or it could lead to disproportionately low muscle strength and power and an increased risk of falls, adverse bone health and frailty fractures, especially in elderly patients (Cava et al., Adv Nutr 2017 May 15;8(3):511-519,. Maintaining skeletal muscle mass can reduce the risk of sarcopenia (Kalinkovich and Livshits, Ageing Res Rev May:35:200-221; 2017).

[0012] Preserving muscle mass while losing weight could contribute to sustaining long-term weight loss by improving the resting metabolic rate (Speakman and Selman, Proc Nutr Soc.

[0013] 2003 Aug;62(3):621-34). In addition, a higher resting metabolic rate could also help achieve more sustained weight loss. Therefore, weight loss treatments that preserve lean mass are hypothesized to improve the quantity, quality, and durability of weight loss.

[0014] Myostatin, referred to as growth differentiation factor-8 (GDF8), is a secreted protein and is a member of the transforming growth factor-beta (TGF-beta) superfamily of proteins. Members of this superfamily possess growth-regulatory and morphogenetic properties (see, e.g., NPL1, NPL2, and PTL1). Myostatin is expressed primarily in the developing and adult skeletal muscle and functions as a negative regulator of muscle growth. Systemic overexpression of myostatin in adult mice leads to muscle wasting (see, e.g., NPL3) while, conversely, a myostatin knockout mouse is characterized by hypertrophy and hyperplasia of the skeletal muscle resulting in two- to threefold greater muscle mass than their wild type littermates (see, e.g., NPL4).

[0015] Like other members of the TGF-beta family, myostatin is synthesized as a large precursor protein containing an N-terminal propeptide domain, and a C-terminal domain considered as the active molecule (see, e.g., NPL5; PTL2). Two molecules of myostatin precursor are covalently linked via a single disulfide bond present in the C-terminal growth factor domain. Active mature myostatin (disulfide-bonded homodimer consisting of the C-terminal growth factor domain) is liberated from myostatin precursor through multiple steps of proteolytic processing. In the first step of the myostatin activation pathway, a peptide bond between the N-terminal propeptide domain and the C-terminal growth factor domain, Arg266-Asp267, is cleaved by a furin-type proprotein convertase in both chains of the homodimeric precursor. But the resulting three peptides (two propeptides and one mature myostatin (i.e., a disulfide-bonded homodimer consisting of the growth factor domains)) remain associated, forming a noncovalent inactive complex that is referred to as "latent myostatin." Mature myostatin can then be liberated from latent myostatin through degradation of the propeptide. Members of the bone morphogenetic protein 1 (BMP1) family of metalloproteinases cleave a single peptide bond within the propeptide, Arg98-Asp99, with concomitant release of mature, active myostatin, a homodimer (see, e.g., NPL6). Moreover, the latent myostatin canbe activated in vitro by dissociating the complex with either acid or heat treatment as well (see, e.g., NPL7).

[0016] Myostatin exerts its effects through a transmembrane serine / threonine kinase heterotetramer receptor family, activation of which enhances receptor transphosphorylation, leading to the stimulation of serine / threonine kinase activity. It has been shown that the myostatin pathway involves an active myostatin dimer binding to the activin receptor type IIB (ActRIIB) with high affinity, which then recruits and activates the transphosphorylation of the low affinity receptor, the activin-like kinase 4 (ALK4) or activin-like kinase 5 (ALK5). It has also been shown that the proteins Smad 2 and Smad 3 are subsequently activated and form complexes with Smad 4, which are then translocated to the nucleus for the activation of target gene transcription. It has been demonstrated that ActRIIB is able to mediate the influence of myostatin in vivo, as expression of a dominant negative form of ActRIIB in mice mimics myostatin gene knockout (see, e.g., NPL8).

[0017] A number of disorders or conditions are associated with muscle wasting (i.e., loss of or functional impairment of muscle tissue), such as muscular dystrophy (MD; including Duchenne muscular dystrophy), amyotrophic lateral sclerosis (ALS), muscle atrophy, Spinal muscular atrophy (SMA); Spinal muscular atrophy with respiratory distress type 1 ; Stiff person syndrome; Troyer syndrome; Guillain-Barre syndrome, organ atrophy, frailty, congestive obstructive pulmonary disease (COPD), sarcopenia, and cachexia resulting from cancer or other disorders, as well as renal disease, cardiac failure or disease, and liver disease. Patients will benefit from an increase in muscle mass and / or muscle strength; however, there are presently limited treatments available for these disorders. Thus, due to its role as a negative regulator of skeletal muscle growth, myostatin becomes a desirable target for therapeutic or prophylactic intervention for such disorders or conditions, or for monitoring the progression of such disorders or conditions. In particular, agents that inhibit the activity of myostatin may be therapeutically beneficial.

[0018] Inhibition of myostatin expression leads to both muscle hypertrophy and hyperplasia (NPL9). Myostatin negatively regulates muscle regeneration after injury and lack of myostatin in myostatin null mice results in accelerated muscle regeneration (see, e.g., NPL10). Anti -myostatin (GDF8) antibodies described in, e.g., PTL3, PTL4, PTL5, PTL6, PTL7, PTL8, PTL9, and PTL10 have been shown to bind to myostatin and inhibit myostatin activity in vitro and in vivo, including myostatin activity associated with the negative regulation of skeletal muscle mass. Myostatin-neutralizing antibodies increase body weight, skeletal muscle mass, and muscle size and strength in the skeletal muscle of wild type mice (see, e.g., NPL11) and the mdx mice, a model for muscular dystrophy (see, e.g., NPL12; NPL13). However, these prior art antibodies are all specific for mature myostatin but not for latent myostatin, and the strategies described for inhibiting myostatin activity have utilized antibodies that can bind to and neutralize mature myostatin. AAV-mediated follistatin, a naturalmyostatin antagonist, gene therapy in the tamoxifen-inducible FSHD mouse model (a disease model that recapitulates the DUX4-dependent myopathic phenotype) resulted in increased muscle mass and strength (Giesige et al. 2018).

[0019] There is a need for additional therapeutic products for the treatment of obesity or overweight.

[0020] In a first aspect, the present invention provides GYM329 / Emugrobart for use in the treatment, prevention, or reduction of obesity or overweight or weight maintenance in a human subject in conjunction with the glucagon-like peptide- 1 receptor (GLP-1) agonist tir-zepatide, wherein the human subject is treated with tirzepatide with a weekly dose of 5 mg, 10 mg or 15 mg and the human subject is treated with the anti-myostatin antibody emugro-bart with a dose of 22.5 mg, 80 mg or 180 mg every 4 weeks.

[0021] In an embodiment of the present invention, emugrobart comprises the six complementary determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 wherein CDRH1 comprises a sequence set forth in SEQ ID 1, CDRH2 comprises a sequence set forth in SEQ ID 2, CDRH3 comprises a sequence set forth in SEQ ID 3, CDRL1 comprises a sequence set forth in SEQ ID 4, CDRL2 comprises a sequence set forth in SEQ ID 5 and CDRL3 comprises a sequence set forth in SEQ ID 6.

[0022] In an embodiment of the present invention, emugrobart comprises a VH chain comprising the amino acid sequence of SEQ ID 7 and a VL chain comprising the amino acid sequence of SEQ ID 8.

[0023] In an embodiment of the present invention, emugrobart comprises a heavy chain comprising the amino acid sequence of SEQ ID 9 and a light chain comprising the amino acid sequence of SEQ. ID. 10.

[0024] In an embodiment of the present invention, emugrobart is administered subcutaneously.

[0025] In an embodiment of the present invention, the human subject suffers from obesity or being overweight with at least one weight-related comorbidity but without diabetes mellitus.

[0026] In an embodiment of the present invention, the human subject is treated for at least 48 weeks.

[0027] In an embodiment of the present invention, the human subject stops treatment with tirzepatide after 48 weeks of treatment with both tirzepatide and emugrobart and continues treatment with a dose of 180 mg every 4 weeks for 24 weeks.

[0028] In a second aspect, the present invention provides Emugrobart and tirzepatide for use in the treatment, prevention, or reduction of obesity or overweight or weight maintenance in a human subject, wherein the human subject is treated with tirzepatide with a weekly doseof 5 mg, 10 mg or 15 mg and the human subject is treated with emugrobart with a dose of 22.5 mg, 80 mg or 180 mg every 4 weeks.

[0029] In an embodiment of the second aspect of the present invention, emugrobart comprises the six complementary determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 wherein CDRH1 comprises a sequence set forth in SEQ ID 1, CDRH2 comprises a sequence set forth in SEQ ID 2, CDRH3 comprises a sequence set forth in SEQ ID 3, CDRL1 comprises a sequence set forth in SEQ ID 4, CDRL2 comprises a sequence set forth in SEQ ID 5 and CDRL3 comprises a sequence set forth in SEQ ID 6.

[0030] In an embodiment of the second aspect of the present invention, emugrobart comprises a VH chain comprising the amino acid sequence of SEQ ID 7 and a VL chain comprising the amino acid sequence of SEQ ID 8.

[0031] In an embodiment of the second aspect of the present invention, emugrobart comprises a heavy chain comprising the amino acid sequence of SEQ ID 9 and a light chain comprising the amino acid sequence of SEQ. ID. 10.

[0032] In an embodiment of the second aspect of the present invention, the anti -myo statin antibody emugrobart is administered subcutaneously.

[0033] In an embodiment of the second aspect of the present invention, the human subject suffers from obesity or overweight with at least one weight-related comorbidity but without diabetes mellitus.

[0034] In an embodiment of the second aspect of the present invention, the human subject is treated for at least 48 weeks.

[0035] In an embodiment of the second aspect of the present invention, the human subject stops treatment with tirzepatide after 48 weeks of treatment with both tirzepatide and emugrobart and continues treatment with a dose of 180 mg every 4 weeks for 24 weeks.

[0036] In a third aspect, the present invention provides a method for the treatment, prevention, or reduction of obesity or overweight or weight maintenance in a human subject, comprising administering to the human subject a glucagon-like peptide-1 receptor (GLP-1) agonist tirzepatide and emugrobart, wherein tirzepatide is administered in a weekly dose of 5 mg, 10 mg or 15 mg and emugrobart is administered every 4 weeks in a dose of 22.5 mg, 80 mg or 180 mg.

[0037] In an embodiment of the third aspect of the present invention, emugrobart comprises the six complementary determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 wherein CDRH1 comprises a sequence set forth in SEQ ID 1, CDRH2 comprises a sequence set forth in SEQ ID 2, CDRH3 comprises a sequence set forth in SEQ ID 3, CDRL1 comprises a sequence set forth in SEQ ID 4, CDRL2 comprises a sequence set forth in SEQ ID 5 and CDRL3 comprises a sequence set forth in SEQ ID 6.In an embodiment of the third aspect of the present invention, emugrobart comprises a VH chain comprising the amino acid sequence of SEQ ID 7 and a VL chain comprising the amino acid sequence of SEQ ID 8.

[0038] In an embodiment of the third aspect of the present invention, emugrobart comprises a heavy chain comprising the amino acid sequence of SEQ ID 9 and a light chain comprising the amino acid sequence of SEQ. ID. 10.

[0039] In an embodiment of the third aspect of the present invention, emugrobart is administered subcutaneously.

[0040] In an embodiment of the third aspect of the present invention, the human subject suffers from obesity or being overweight with at least one weight-related comorbidity but without diabetes mellitus.

[0041] In an embodiment of the third aspect of the present invention, the human subject is treated for at least 48 weeks.

[0042] In an embodiment of the third aspect of the present invention, the human subject stops treatment with tirzepatide after 48 weeks of treatment with both tirzepatide and emugrobart and continues treatment with a dose of emugrobart of 180 mg every 4 weeks for 24 weeks.

[0043] In a fourth aspect, the present invention provides tirzepatide the for use in the treatment, prevention, or reduction of obesity or overweight or weight maintenance in a human subject, wherein the treatment comprises administration of tirzepatide in conjunction with the anti-myostatin antibody emugrobart, wherein the human subject is treated with tirzepatide with a weekly dose of 5 mg, 10 mg or 15 mg and the human subject is treated with the anti -myo statin antibody emugrobart with a dose of 22.5 mg, 80 mg or 180 mg every 4 weeks.

[0044] In an embodiment of the fourth aspect of the present invention, emugrobart comprises the six complementary determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 wherein CDRH1 comprises a sequence set forth in SEQ ID 1, CDRH2 comprises a sequence set forth in SEQ ID 2, CDRH3 comprises a sequence set forth in SEQ ID 3, CDRL1 comprises a sequence set forth in SEQ ID 4, CDRL2 comprises a sequence set forth in SEQ ID 5 and CDRL3 comprises a sequence set forth in SEQ ID 6.

[0045] In an embodiment of the fourth aspect of the present invention, emugrobart comprises a VH chain comprising the amino acid sequence of SEQ ID 7 and a VL chain comprising the amino acid sequence of SEQ ID 8.

[0046] In an embodiment of the fourth aspect of the present invention, emugrobart comprises a heavy chain comprising the amino acid sequence of SEQ ID 9 and a light chain comprising the amino acid sequence of SEQ. ID. 10.In an embodiment of the fourth aspect of the present invention, emugrobart is administered subcutaneously.

[0047] In an embodiment of the fourth aspect of the present invention, the human subject suffers from obesity or being overweight with at least one weight-related comorbidity but without diabetes mellitus.

[0048] In an embodiment of the fourth aspect of the present invention, the human subject is treated for at least 48 weeks.

[0049] In an embodiment of the fourth aspect of the present invention, the human subject stops treatment with tirzepatide after 48 weeks of treatment with both tirzepatide and emugrobart and continues treatment with a dose of emugrobart of 180 mg every 4 weeks for 24 weeks.

[0050] Detailed Description

[0051] All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0052] The nomenclature used in the present application is based on IPUAC systematic nomenclature, unless indicated otherwise.

[0053] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, N.Y. 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, N.Y. 1992), provide one skilled in the art with a general guide to many of the terms used in the present application. All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.

[0054] For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

[0055] An "individual" or "subject", used interchangeably, is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non- human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human. In a particular embodiment of the invention the subject is a human with obesity.The term "patient" refers to a human (such as a male or female human) who has been diagnosed with obesity.

[0056] The term "active pharmaceutical ingredient" (or "API") denotes the compound or molecule in a pharmaceutical composition that has a particular biological activity.

[0057] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.

[0058] The term "pharmaceutical composition" refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered. The term "pharmaceutically acceptable" denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is The term “Cmax” (expressed in units of ng / mL) means maximum observed plasma concentration.

[0059] The term “Tmax” (expressed in units of hours, or as a median number of hours for Tmax in the study population) means the observed time to reach Cmax following drug administration; if it occurs at more than one time point Tmax is defined as the first time point with this value.

[0060] The term “AUCT0-24h” (expressed in units of ng h / mL) means the area under the plasma concentration time curve (AUC).

[0061] The term “buffer” or “buffer system” denotes a pharmaceutically acceptable excipient or excipient mixture, which stabilizes the pH of a pharmaceutical preparation. Suitable buffers are well known in the art and can be found in the literature. Particular pharmaceutically acceptable buffers comprise citric buffer, malate buffer, maleate buffer, or tartrate buffer, most particularly tartrate buffer. Particular buffer systems of the invention combinations of organic acid and selected salts thereof, e.g. tribasic sodium citrate and citric acid, malic acid and sodium malate, potassium sodium tartrate and tartaric acid, or disodium tartrate and tartaric acid, particularly potassium sodium tartrate and tartaric acid. Alternatively, the organic acid (particularly tartaric acid) can be employed alone as “acidifier” instead of the combination of acid and the corresponding salt. Independently from the buffer used, the pH can be adjusted with an acid or a base known in the art, e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid and citric acid, sodium hydroxide and potassium hydroxide. Particular acidifier is tartaric acid.The term “antioxidant” denotes pharmaceutically acceptable excipients, which prevent oxidation of the active pharmaceutical ingredient. Antioxidants comprise ascorbic acid, glutathione, cysteine, methionine, vitamin E TPGS, EDTA.

[0062] The term "therapeutically effective amount," as used herein, refers to an amount of a compound sufficient to treat, ameliorate, or prevent the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect. The effect can be detected by, for example, an improvement in clinical condition, or reduction in symptoms. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Where a drug has been approved by the U.S. Food and Drug Administration (FDA), a "therapeutically effective amount" refers to the dosage approved by the FDA or its counterpart foreign agency for treatment of the identified disease or condition.

[0063] As used herein, a patient “in need of GYM329 therapy" (or “in need of an anti-myo-statin antibody therapy”) is a patient who would benefit from administration of GYM329.

[0064] “GYM329” also known as RO7204239 or emugrobart according to the present invention refers to an “anti-myostatin antibody”, wherein the antibody comprises six complementary determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 wherein CDRH1 comprises a sequence set forth in SEQ ID 1, CDRH2 comprises a sequence set forth in SEQ ID 2, CDRH3 comprises a sequence set forth in SEQ ID 3, CDRL1 comprises a sequence set forth in SEQ ID 4, CDRL2 comprises a sequence set forth in SEQ ID 5 and CDRL3 comprises a sequence set forth in SEQ ID 6. GYM329 can also be defined by a heavy chain variable region comprising an amino acid sequence of SEQ ID 7 and light chain variable region comprising an amino acid sequence of SEQ ID 8. Methods of making and using GYM 329 are described in can be produced according to WO2016098357 and WO2017 / 104783. GYM 329 is known to be Fc engineered to enable remove antigen from plasma.

[0065] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell but may contain mutations. Mutant progeny that has the same function or biological activity as screened or selected for in the originally transformed cell are included herein.The terms "anti -myo statin antibody" and "an antibody that binds to myostatin" refer to an antibody that is capable of binding myostatin with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting myostatin. In one embodiment, the extent of binding of an anti-myostatin antibody to an unrelated, non-myostatin protein is less than about 10% of the binding of the antibody to myostatin as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to myostatin has a dissociation constant (Kd) of 1 micro M or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10-8 M or less, e.g., from 10-8 M to 10-13 M, e.g., from 10-9 M to 10-13 M). In certain embodiments, an anti myostatin antibody binds to an epitope of myostatin that is conserved among myostatin from different species.

[0066] The term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.

[0067] An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay, and / or conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay. An exemplary competition assay is provided herein.

[0068] A "human antibody" is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a nonhuman source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non -human antigen-binding residues.

[0069] The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl , IgG2 , IgG3 , IgG4 , IgAl , and IgA2 . The heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.

[0070] The term "epitope" includes any determinant capable of being bound by an antibody. An epitope is a region of an antigen that is bound by an antibody that targets that antigen and includes specific amino acids that directly contact the antibody. Epitope determinants can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have specific three dimensional structural characteristics, and / or specific charge characteristics. Generally, antibodies specific fora particular target antigen will preferentially recognize an epitope on the target antigen in a complex mixture of proteins and / or macromolecules.

[0071] The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl -terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0072] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0073] The terms "full length antibody," "intact antibody," and "whole antibody" are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

[0074] The term "myostatin", as used herein, may refer to any native myostatin from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). Unless otherwise indicated, the term "myostatin " refers to a human myostatin protein having the amino acid sequence shown in SEQ ID NO: 11 and containing the terminal propeptide domain of human myostatin as shown in SEQ ID NO: 12 or 13. The term encompasses "full-length", unprocessed myostatin as well as any form of myostatin that results from processing in the cell. The term also encompasses naturally occurring variants of myostatin, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human myostatin (promyo statin) is shown in SEQ ID NO: 11. The amino acid sequence of an exemplary N-terminal propeptide domain of human myostatin is shown in SEQ ID NO: 12 or 13. Active mature myostatin is a disulfide-bonded homodimer consisting of two C-terminal growth factor domains. Inactive latent myostatin is a noncovalently-associ-ated complex of two propeptides and the mature myostatin. As disclosed herein, the antibodies of the invention bind inactive latent myostatin, but do not bind the mature active myostatin homodimer. In some embodiments, the antibodies of the invention bind an epitope within a fragment consisting of amino acids 21-100 of myostatin propeptide (SEQ ID NO: 13), but do not bind the mature active myostatin homodimer.The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0075] The term "vector," as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-repli-cating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors".

[0076] The term "hypervariable region" or "HVR" as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence ("complementarity determining regions" or "CDRs") and / or form structurally defined loops ("hypervariable loops") and / or contain the antigen-contacting residues ("antigen contacts"). Generally, antibodies comprise six HVRs: three in the VH (Hl, H2, H3), and three in the VL (LI, L2, L3). Exemplary HVRs herein include: (a) hypervariable loops occurring at amino acid residues 26-32 (LI), 50-52 (L2), 91-96 (L3), 26-32 (Hl), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (LI), 50-56 (L2), 89-97 (L3), 31-35b (Hl), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, NIH, Bethesda, MD (1991)); (c) antigen contacts occurring at amino acid residues 27c-36 (LI), 46-55 (L2), 89-96 (L3), 30-35b (Hl), 47-58 (H2), and 93-101 (H3) (MacCallum et al., J. Mol. Biol. 262: 732-745 (1996)); and (d) combinations of (a), (b), and / or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (Hl), 26-35b (Hl), 49-65 (H2), 93-102 (H3), and 94-102 (H3). Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0077] Table 1: Anti-Myostatin Antibody GYM329 / emugrobart CDR sequences

[0078]

[0079]

[0080] Table 2: Anti-Myostatin Antibody GYM329 / emugrobart amino acid sequences

[0081]

[0082]

[0083] The following examples are intended merely to illustrate the practice of the present invention and are not provided by way of limitation.

[0084] Example 1:

[0085] The study is designed to evaluate the efficacy, safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of GYM329 / Emugrobart / RO7204239 in combination with tirzepatide in adults with obesity or overweight with at least one weight-related comorbidity, but without diabetes mellitus. To ensure thorough assessment of RO7204239 and its properties clinically, the study comprises 4 main periods: a 4-week screening period, a 48- week core treatment period, a 24-week treatment extension period, and a 24-week posttreatment follow-up (FU) period. These additional periods will be used to evaluate the effect of RO7204239 on weight maintenance without concomitant as well as off-treatment incretin.

[0086] Primary and secondary endpoints

[0087]

[0088]

[0089] Abbreviations: ADA = anti-drug antibodies; AE = adverse event; AU Ctau, ss= steady-state area underthe concentrationtime curve over one dosing interval; BMI =body mass index; CL / F =apparent clearance; Cmax, ss = steady-state maximum concentration; Ctrough,ss = steady-state trough concentration; DXA=dual-energy X-ray absorptiometry;

[0090] ECG = electrocardiogram; HbA1c=glycated hemoglobin; HDL = high-density lipoprotein; HOMA-IR = Homeostasis Model Assessment of Insulin Resistance; LDL = low-density lipoprotein; MRI = magnetic resonance imaging;

[0091] NCI CTCAE, v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events v5.0;

[0092] PK= pharmacokinetics; QUICKI = Quantitative Insulin Sensitivity Check Index; SC = subcutaneous; ti / 2 = half-life; Vd / F =apparent volume of distribution.

[0093] Overall trial design

[0094] Screening:During the screening period, eligibility prior to enrollment into the study will be determined. Eligible participants will be randomized into 1 of the 4 treatment arms.

[0095] 48-Week Core- and 24-Week Extension -treatment Periods:

[0096] All participants will receive tirzepatide as background treatment in the core treatment period. In addition, they will be randomized into one of the following four treatment arms: placebo arm, or RO720423922.5 mg, 80 mg, or 180 mg Q4W arms (2:2:2:3, respectively). All participants will receive tirzepatide up-titrated according to the approved tirzepatide prescribing information. Tirzepatide can be self-administered QW at home, while RO7204239 or placebo will be administered SC Q4W at the study site. At study visits both treatments will be administered at the study site. The primary analysis will occur after the 48-week core treatment period.

[0097] Following the core treatment period of 48 weeks, all participants will stop treatment with tirzepatide and enter the 24-week treatment extension period. All participants will be re-randomized to maintain the study blind. Participants originally assigned to RO7204239 180 mg Q4W will be re-randomized (1:1) to receive either 180 mg RO7204239 Q4W or placebo Q4W for 24 weeks to assess the effect of RO7204239 on maintenance of any body weight lost and physical parameters. All other participants will complete the re-randomiza-tion procedure and receive placebo for 24 weeks to maintain the study blind.

[0098] 24-Week Post-Treatment Follow-Up Period:

[0099] After the treatment-extension period, all study treatments will be discontinued, and participants will enter a 24-week post-treatment FU period.

[0100] Description of Trial Population and rationale

[0101] The participants in this study will be adults with obesity or overweight with at least one weight-related comorbidity, without diabetes mellitus, and who fulfill all of the given inclusion criteria and none of the exclusion criteria.

[0102] Prospective approvals of protocol deviations, as related to inclusion and / or exclusion criteria, also known as protocol waivers or exemptions, are not permitted.

[0103] Inclusion Criteria

[0104] Participants are eligible to be included in the study only if all of the following criteria apply:

[0105] Male or female participants, aged 18 and above at the time of signing the ICF.

[0106] Type of Participants, Weight, and Disease Characteristics

[0107] 1. Participants must have at screening:a) BMI>30.0 kg / m2(additional weight-related comorbidities are not required for inclusion).

[0108] OR

[0109] b) BMI>27.0 kg / m2and <30.0 kg / m2with at least one weight-related comorbidity such as:

[0110] o Prediabetes: defined as glycated hemoglobin (HbAlc) 5.7% to 6.4% (39 to 47 mmol / mol), or fasting plasma glucose 100 mg / dL to 125 mg / dL (5.6-6.9 mmol / L), as defined by the 2024 American Diabetes Association Standards of Medical Care in Diabetes.

[0111] o Hypertension: defined as current use of blood pressure lowering agents initiated for hypertension, or with systolic blood pressures 130 mmHg or diastolic blood pressure >80 mmHg.

[0112] o Dyslipidemia: defined as current use of lipid-lowering agents initiated for dyslipidemia, or with low-density lipoprotein (LDL) > 160 mg / dL (4.1 mmol / L) or triglycerides >150 mg / dL (1.7 mmol / L), or high-density lipoprotein (HDL) <40 mg / dL (1.0 mmol / L) for men or HDL<50 mg / dL (1.3 mmol / L) for women, based on central laboratory value.

[0113] o Diagnosis of obstructive sleep apnea.

[0114] o Cardiovascular disease: (e.g., ischemic cardiovascular disease, New York Heart Association [NYHA] Functional Classification Class I-II heart failure).

[0115] 2. History of at least one self-reported unsuccessful dietary or exercise effort to lose body weight.

[0116] 3. Weight stability: self-reported change in body weight less than 5 kg (11 lbs) within

[0117] 3 months prior to screening.

[0118] Sex and Contraception / Barrier Requirements

[0119] Section 1.01 Exclusion Criteria

[0120] Participants are excluded from the study if any of the following criteria apply:

[0121] 1. Pregnant or breastfeeding, or with intention of becoming pregnant during the study or within the time frame in which contraception is required.

[0122] • POCBP are required to have a serum pregnancy test at screening and urine pregnancy test on Day 1 before randomization.

[0123] Medical Conditions

[0124] Diabetes Related

[0125] 2. Prior history or diagnosis of diabetes mellitus (T1DM, T2DM, or rare forms of diabetes mellitus) or historical or screening laboratory values suggestive of diabetes mellitus, defined as 1 or more values of HbAlc>6.5% (48 mmol / mol), fasting serum glucose> 126 mg / dL (7.0 mmol / L), or random glucose>200 mg / dL (11.1 mmol / L). Participants with fully resolved gestational diabetes mellitus are eligible. Note: diagnosis of prediabetes (determined by fasting glucose or HbAlc) is not exclusionary, but participants must not be on any type of glucose-lowering treatments (pharmacologic or dietary supplements), including but not limited to metformin and berberine.3. Presence of non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy or diabetic macular edema.

[0126] Weight Related

[0127] 4. Have obesity induced by other endocrinologic disorders (e.g., Cushing’s syndrome) or diagnosed monogenetic or syndromic forms of obesity (e.g., melanocortin 4 receptor deficiency [MC4R] or Prader-Willi Syndrome).

[0128] 5. Participation in unbalanced / extreme diets (e.g., very low calorie, low carbohydrate, very high protein, ketogenic diets) or in an organized weight reduction program within 3 months of the screening visit or plans to engage in such diets or programs during the study.

[0129] 6. Prior or planned surgical treatment for obesity (excluding liposuction or abdominoplasty if performed > 1 year prior to screening).

[0130] 7. Endoscopic and / or device-based therapy for obesity or device removal within 6 months prior to screening, including but not limited to mucosal ablation, gastric artery embolization, in- tragastric balloon, and duodenal-jejunal endoluminal liner.

[0131] 8. Have a known clinically significant gastric emptying abnormality (e.g., severe gastroparesis or gastric outlet obstruction), have undergone gastric bypass (bariatric) surgery or restrictive bariatric surgery (e.g., LAP-BAND®), or chronically take drugs that directly affect gastrointestinal motility.

[0132] Cardiovascular Related

[0133] 9. Have any of the following cardiovascular conditions within 6 months prior to screening: a) Acute myocardial infarction,

[0134] b) Cerebrovascular accident (stroke),

[0135] c) Unstable angina, or

[0136] d) Hospitalization due to congestive heart failure.

[0137] 10. Ongoing or history of intermittent or chronic tachyarrhythmia syndromes (e.g., atrial fibrillation, supraventricular tachycardia, and positional orthostatic tachycardia syndrome). Note: Participants with a history of premature atrial contractions or premature ventricular contractions may be included.

[0138] 11. Have a history of NYHA Functional Classification III or IV congestive heart failure.

[0139] 12. Have a personal or family history of long QT syndrome, family history of sudden death before the age of 40 years in a first-degree relative (parents, siblings, or children), or a personal history of unexplained syncope within 1 year prior to screening. Use of prescription or over-the-counter (OTC) medications known to significantly prolong the QT or QTc interval at screening.

[0140] Tirzepatide- related

[0141] 13. Have a history of acute or chronic pancreatitis. A participant with a history of acute pancreatitis caused by gallstones may be included in the study if the participant has had a cholecystectomy to resolve the problem.

[0142] 14. Have a history of clinically significant gallbladder disease. However, participants with cholecystectomy may be included in the study.

[0143] 15. Have a history of significant active or unstable moderate to severe major depressive disorder (MDD) or other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder, or other serious mood or anxiety disorder or a suicide attempt) within the last 2 years of screening.16. Have a known personal or family history (first-degree relative) of multiple endocrine neoplasia type 2A or type 2B, thyroid C-cell hyperplasia, or medullary thyroid carcinoma. Other Medical Related Exclusions

[0144] 17. Have evidence of significant active, uncontrolled cardiovascular, autoimmune, endocrine, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, a neurological or psychiatric condition, or a history of any medical condition capable of constituting a risk when taking the study medication or interfering with the interpretation of data, as judged by the Investigator at screening.

[0145] 18. Have evidence of hypothyroidism or hyperthyroidism based on clinical evaluation and / or an abnormal thyroid-stimulating hormone that, in the opinion of the Investigator, would pose a risk to participant’s safety. Participants on a stable dose of thyroid replacement therapy for at least the prior 3 months who are clinically euthyroid and who are anticipated to remain on this dose throughout the study period may be eligible if they meet the other criteria.

[0146] 19. Have evidence of a significant, uncontrolled endocrine abnormality (e.g., thyrotoxicosis and adrenal crises).

[0147] 20. Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years prior to screening.

[0148] 21. Have had a transplanted organ (comeal transplants [keratoplasty] are allowed) or are awaiting an organ transplant.

[0149] 22. Have had a blood donation of >500 mL within 8 weeks prior to screening or a blood transfusion or severe blood loss within 3 months prior to screening or have known hemoglobinopathy which may lead to anemia in the opinion of the Investigator during the course of the study (e.g., hemolytic anemia, sickle cell anemia).

[0150] 23. Have evidence of a significant, active autoimmune abnormality (e.g., lupus or rheumatoid arthritis) that has required (within the last 3 months) or is likely to require, in the opinion of the Investigator, concurrent treatment with systemic glucocorticoids (excluding topical, intraocular, intranasal, intra-articular or inhaled preparations) during study participation. 24. Clinically significant allergies to humanized mAbs or multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (e.g., erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis).

[0151] Prior / Concomitant Therapy

[0152] 25. Live vaccine(s) within one month prior to screening or plans to receive live vaccines during the study or within 28 days of the last study treatment administration

[0153] 26. Treatment with biologic agents (such as mAbs including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to first dose.

[0154] 27. Have current or previous use 6 months prior to screening or plan to be treated during the study participation with any pharmacotherapy, dietary supplements, or any OTC preparations for obesity that promote weight loss or glucose metabolism. Have current or previous use within 6 months of the screening visit or plan to be treated during the study participation with any treatment that may cause significant weight gain.28. Are currently taking a central nervous system stimulant (e.g., Ritalin-SR), with the exception of caffeinated beverages.

[0155] 29. Have started or changed the dose of antihyperlipidemic medications within 3 months before the screening visit.

[0156] 30. Are receiving or have received within 3 months before the screening visit chronic ( > 14 consecutive days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, intraarticular, or inhaled preparations).

[0157] 31. Have a known allergy to any component of the study treatment (i.e. , RO7204239 / RO7204239 placebo or tirzepatide) formulation or any other condition not listed in this section (e.g., hypersensitivity or intolerance) that is a contraindication to GLP-lRAs or GLP- 1 / GIP RAs.

[0158] Prior / Concurrent Clinical Study Experience

[0159] 32. Participants who are currently enrolled in any other clinical study involving an investigational product (IP) or any other type of medical research deemed scientifically or medically incompatible with this study, or who have received any investigational medicinal product (IMP) within 90 days prior to Day 1 or less than 5 elimination half-lives prior to Day 1 (whichever is longer).

[0160] 33. Participants who have previously received RO7204239.

[0161] Summary of Treatments Administered

[0162]

[0163] Abbreviation: Q4W= every 4 weeks

Claims

Claims1. Emugrobart for use in the treatment, prevention, or reduction of obesity or overweight or weight maintenance in a human subject in conjunction with the glucagon-like peptide- 1 receptor (GLP-1) agonist tirzepatide, wherein the human subject is treated with tirzepatide with a weekly dose of 5 mg, 10 mg or 15 mg and the human subject is treated with the anti-myostatin antibody emugrobart with a dose of 22.5 mg, 80 mg or 180 mg every 4 weeks.

2. Emugrobart for use according to claim 1, wherein the emugrobart comprises the six complementary determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 wherein CDRH1 comprises a sequence set forth in SEQ ID 1, CDRH2 comprises a sequence set forth in SEQ ID 2, CDRH3 comprises a sequence set forth in SEQ ID 3. CDRL1 comprises a sequence set forth in SEQ ID 4, CDRL2 comprises a sequence set forth in SEQ ID 5 and CDRL3 comprises a sequence set forth in SEQ ID 6.

3. Emugrobart for use according to claim 1 or 2, wherein emugrobart comprises a VH chain comprising the amino acid sequence of SEQ ID 7 and a VL chain comprising the amino acid sequence of SEQ ID 8.

4. Emugrobart for use according to claims 1 to 3, wherein emugrobart comprises a heavy chain comprising the amino acid sequence of SEQ ID 9 and a light chain comprising the amino acid sequence of SEQ. ID. 10.

5. Emugrobart for use according to claims 1 to 4, wherein emugrobart is administered subcutaneously.

6. Emugrobart for use according to claims 1 to 5, wherein the human subject suffers from obesity or overweight with at least one weight-related comorbidity but without diabetes mellitus.

7. Emugrobart for use according to claims 1 to 6, wherein the human subject is treated for at least 48 weeks.

8. Emugrobart for use according to claims 1 to 7, wherein the human subject stops treatment with tirzepatide after 48 weeks of treatment with both tirzepatide and emugrobart and continues treatment with a dose of emugrobart of 180 mg every 4 weeks for 24 weeks.

9. Emugrobart and tirzepatide for use in the treatment, prevention, or reduction of obesity or overweight or weight maintenance in a human subject, wherein the human subject is treated with tirzepatide with a weekly dose of 5 mg, 10 mg or 15 mg and the human subject is treated with emugrobart with a dose of 22.5 mg, 80 mg or 180 mg every 4 weeks.

10. Emugrobart and tirzepatide for use according to claim 9, wherein emugrobart comprises the six complementary determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 wherein CDRH1 comprises a sequence set forth in SEQ ID 1, CDRH2 comprises a sequence set forth in SEQ ID 2, CDRH3 comprises a sequence set forth in SEQ ID 3, CDRL1 comprises a sequence set forth in SEQ ID 4, CDRL2 comprises a sequence set forth in SEQ ID 5 and CDRL3 comprises a sequence set forth in SEQ ID 6.

11. Emugrobart and tirzepatide for use according to claim 9 or 10, wherein emugrobart comprises a VH chain comprising the amino acid sequence of SEQ ID 7 and a VL chain comprising the amino acid sequence of SEQ ID 8.

12. Emugrobart and tirzepatide for use according to claims 9 to 11, wherein emugrobart comprises a heavy chain comprising the amino acid sequence of SEQ ID 9 and a light chain comprising the amino acid sequence of SEQ. ID. 10.

13. Emugrobart and tirzepatide for use according to claims 9 to 12, wherein the anti-myostatin antibody emugrobart is administered subcutaneously.

14. Emugrobart and tirzepatide for use according to claims 9 to 13, wherein the human subject suffers from obesity or overweight with at least one weight-related comorbidity but without diabetes mellitus.

15. Emugrobart and tirzepatide for use according to claims 9 to 14, wherein the human subject is treated for at least 48 weeks.

16. Emugrobart and tirzepatide for use according to claims 9 to 15, wherein the human subject stops treatment with tirzepatide after 48 weeks of treatment with both tirzepatide and emugrobart and continues treatment with a dose of emugrobart of 180 mg every 4 weeks for 24 weeks.

17. A method for the treatment, prevention, or reduction of obesity or overweight or weight maintenance in a human subject, comprising administering to the human subject a glucagon-like peptide- 1 receptor (GLP-1) agonist tirzepatide and emugrobart, wherein tirzepatide is administered in a weekly dose of 5 mg, 10 mg or 15 mg and emugrobart is administered every 4 weeks in a dose of 22.5 mg, 80 mg or 180 mg.

18. The method of claim 17, wherein emugrobart comprises the six complementary determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 wherein CDRH1 comprises a sequence set forth in SEQ ID 1, CDRH2 comprises a sequenceset forth in SEQ ID 2, CDRH3 comprises a sequence set forth in SEQ ID 3, CDRL1 comprises a sequence set forth in SEQ ID 4, CDRL2 comprises a sequence set forth in SEQ ID 5 and CDRL3 comprises a sequence set forth in SEQ ID 6.

19. The method of claim 18, wherein emugrobart comprises a VH chain comprising the amino acid sequence of SEQ ID 7 and a VL chain comprising the amino acid sequence of SEQ ID 8.

20. The method of claim 19, wherein emugrobart comprises a heavy chain comprising the amino acid sequence of SEQ ID 9 and a light chain comprising the amino acid sequence of SEQ. ID. 10.

21. The method of claims 17 - 19, wherein emugrobart is administered subcutaneously.

22. The method of claims 17 - 21, wherein the human subject suffers from obesity or overweight with at least one weight-related comorbidity but without diabetes mellitus.

23. The method of claims 17 - 22, wherein the human subject is treated for at least 48 weeks.

24. The method of claims 17 - 23, wherein the human subject stops treatment with tir-zepatide after 48 weeks of treatment with both tirzepatide and emugrobart and continues treatment with a dose of emugrobart of 180 mg every 4 weeks for 24 weeks.

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